1. Field of the Invention
The present invention relates to soft and hard shell gelatin capsules encapsulating a pharmaceutically acceptable fill containing acetaminophen.
Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. Filled one-piece softgels have been widely known and used for many years and for a variety of purposes. Because softgels have properties that are quite different from telescoping two-piece, hard shell capsules, the softgels are capable of retaining a liquid fill material. The fill material may vary from industrial adhesives to bath oils. More commonly, however, the softgels are used to enclose consumable materials such as vitamins and pharmaceuticals in a liquid vehicle or carrier.
A particularly good bioavailability of the pharmacologically active substance is attained if the active substance is successfully dissolved in a suitable solvent and the encapsulated solution is administered to the patient. The term "active substance" as used herein describes any active substance that can be orally administered in capsule form. This term includes pharmaceuticals, dietary supplements, vitamins and the like.
Solutions also provide the best liquid form to obtain optimal "content uniformity" in softgel fill. In addition, a solution provides a faster and more uniform absorption of a pharmaceutical agent than a suspension. Because of these distinct technical advantages, solutions are preferred over suspensions or other dispersions.
Producing a highly concentrated solution of any acidic, amphoteric or basic pharmaceutical agent is useful because it permits the encapsulation of a unit dose of the pharmaceutical agent in a softgel capsule that is small enough to permit easy swallowing. Filling a unit dose in a small softgel capsule to permit easy swallowing is useful because it increases patient acceptance of the medication. Patient acceptance is especially important in the case of medications, because patient acceptance of the medication is a substantial step towards solving one of the major problems of drug therapy--patient noncompliance with the prescribed regimen.
A further utility of highly concentrated solutions is enhancement of bioavailability of the dissolved pharmaceutical agent. Enhanced bioavailability occurs as a result of delivering the pharmaceutical agent already in solution at the site of absorption, permitting a faster and more uniform absorption to occur.
However, a problem in the art is that an appropriate solution of the pharmaceutical agent cannot always be achieved. One constraint is size. Often, it is not possible to dissolve the pharmaceutical agent in a volume of solvent small enough to produce a softgel that is appropriate from the standpoint of economics and patient acceptance. Another constraint, is the solvent itself. The solvent must have sufficient solvating power to dissolve a large amount of the pharmaceutical agent to produce a highly concentrated solution, and yet not hydrolyze, dissolve, or tan the softgel capsule shell.
In many cases, this problem would have been solved by using the enhanced solubility system described in U.S. Pat. No. 5,071,643. U.S. Pat. No. 5,071,643 (Yu et al.) discloses, inter alia, soft gelatin capsules containing highly concentrated acetaminophen solutions comprising 25-40% by weight acetaminophen, 0.4-1.0 moles of hydroxide ion per mole of acetaminophen (provided, for example, by potassium hydroxide), and 1-20% by weight water in a polyethylene glycol base, such as PEG 600. A specific example of a 35% concentrated solution of acetaminophen is shown in Example VI of this patent. However, it has been recently determined that the sodium hydroxide or potassium hydroxide required to solubilize the acetaminophen at very high concentrations increased the pH of the polyethylene glycol solution to greater than 12. This resulted in the degradation of the acetaminophen and the dissolving of the softgel shell.
Thus, the problem of finding an appropriate solvent system for a soft gelatin capsule fill still exists for acetaminophen. It has been difficult to achieve a soft gelatin capsule of small enough size to be acceptable to patients, i.e., small enough to swallow, while still including in that capsule a sufficient amount of acetaminophen in solution to provide an effective unit dose. Thus, there is a need in the art for a soft gelatin capsule containing a fill in which acetaminophen is dissolved in a solvent system in a high enough concentration to provide an effective unit dose in a patient acceptable size capsule while at the same time avoiding degradation of the acetaminophen and the capsule shell.